benefit risk analysis

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Mapi 2013, All rights reserved 3

EU PV Changes to PSURs &Strategies for Benefit-Risk Analysis

Hemendra Misra MD, MPH, MSc, Senior Director, ProductRisk Management

William C. Maier MPH, PHD, Chief Scientific Officer

29 May 2013


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Hemendra Misra MD, MPH, MSc

Senior Director, Product Risk Management

GERMANY

Pharmacovigilance Physician with seventeen years of international work experience

Nine years of Industry experience (Pharma & CRO) - Medical Monitor, Drug SafetyPhysician, Safety Expert, Risk Management Expert

Took a lead scientific, commercial and organizational role in the development of safetyand risk management services for both new and existing pharmaceutical companyclients

Medical practice includes positions in hospitals in India and with Medecines SansFrontieres (Doctors Without Borders)

Public health experience:

Consultant for a WHO Anti-Malaria program in India

Member of the STB SARS Containment Team in Singapore

Medical Officer for the Health Promotion Board in Singapore

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William C. Maier, PhD

Chief Scientific OfficerUK

Over 20 years experience in biopharmaceuticalindustry with specialty in the design, analysis,and interpretation for epidemiology &observational studiesEditor PharmacoEPI and Risk ManagementNewsletter www.prmnewsletter.orgFrequent international speaker on Epidemiology,Health Technology Assessment, Drug Safety and RiskManagementPreviously Senior Director of Epidemiology at GSK and Elan

PharmaceuticalsEMEA Working Group MemberNetwork of Pharmacoepidemiology Centres in EU EnCEPP Project

Specialties Respiratory, Endocrinology, Gastrointestinal,Autoimmune, Vaccines, Oncology


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Agenda

Topic Presenter

The new PSUR and itsrequirements

Hemendra Misra

Challenges in preparing the PSUR Hemendra Misra

Strategies for presenting thebenefit-risk analysis

Will Maier

Summary Hemendra Misra

Questions Hemendra Misra & Will Maier


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Section 1The new PSUR and its

requirements



The new PSUR - Definition

Periodic safety update reports (PSURs) arepharmacovigilance documents intended to providean evaluation of the risk-benefit balance of amedicinal product. They shall be submitted bymarketing authorisation holders at defined timepoints during the post-authorisation phase.



Legal basis for the PSUR

Regulation (EU) No 1235/2010Directive 2010/84/EU

Commission Implementing Regulation (EU) No520/2012

Guidance on scope, objectives, format andcontent of the PSUR

European Medicines Agency (EMA) Guideline on goodpharmacovigilance practices (GVP) Module VII

Periodic safety update report

based on those for the Periodic Benefit Risk EvaluationReport (PBRER) described in the ICH-E2C(R2) guideline



Structure of the PSURPart I: Title page including signature

Part II: Executive Summary

Part III: Table of Contents

1. Introduction

2. Worldwide marketing authorisation status

3. Actions taken in the reporting interval for safety reasons

4. Changes to reference safety information

5. Estimated exposure and use patterns

5.1. Cumulative subject exposure in clinical trials

5.2. Cumulative and interval patient exposure from marketing experience

6. Data in summary tabulations

6.1. Reference information

6.2. Cumulative summary tabulations of serious adverse events from clinical trials

6.3. Cumulative and interval summary tabulations from post-marketing data sources

7. Summaries of significant findings from clinical trials during the reporting interval

7.1. Completed clinical trials

7.2. Ongoing clinical trials

7.3. Long-term follow-up

7.4. Other therapeutic use of medicinal product

7.5. New safety data related to fixed combination therapies

8. Findings from non-interventional studies

9. Information from other clinical trials and sources

9.1. Other clinical trials

9.2. Medication errors

10. Non-clinical Data



Structure of the PSUR (2)11. Literature

12. Other periodic reports

13. Lack of efficacy in controlled clinical trials

14. Late-breaking information

15. Overview of signals: new, ongoing or closed

16. Signal and risk evaluation

16.1. Summaries of safety concerns

16.2. Signal evaluation

16.3. Evaluation of risks and new information

16.4. Characterisation of risks

16.5. Effectiveness of risk minimisation (if applicable)

17. Benefit evaluation

17.1. Important baseline efficacy and effectiveness information

17.2. Newly identified information on efficacy and effectiveness

17.3. Characterisation of benefits

18. Integrated benefit-risk analysis for authorised indications

18.1. Benefit-risk context Medical need and important alternatives

18.2. Benefit-risk analysis evaluation

19. Conclusions and actions

20. Appendices to the PSUR



Key Changes to the PSUR

Objective, format, content, timelines

New section on Benefit-risk evaluation

New section on Safety Signals

No routine line-listings required

No PSURs required for certain category of productsgeneric medicinal products

well-established use medicinal products

homeopathic medicinal products

traditional herbal medicinal products

Operational aspects



Potential sources of information for the PSUR(efficacy, effectiveness, safety information)

non-clinical studies

spontaneous reports (e.g. on the marketing authorisation holders safetydatabase)

active surveillance systems (e.g. sentinel sites)

investigations of product quality

product usage data and drug utilisation information

clinical trials, including research in unauthorised indications or populations

observational studies, including registries

patient support programs

systematic reviews and meta-analysis

marketing authorisation holders sponsored websites

published scientific literature or reports from abstracts, including information

presented at scientific meetingsunpublished manuscripts

licensing partners, other sponsors or academic institutions and researchnetworks

competent authorities (worldwide)



Overview of Signals



Safety Signal Evaluation

source or trigger of the signal

background relevant to the evaluation

method(s) of evaluation, including data sources, search criteria (whereapplicable, the specific MedDRA terms (e.g. PTs, HLTs, SOCs, etc.) orStandardised MedDRA Queries (SMQs) that were reviewed), and analytical

approaches

results - a summary and critical analysis of the data considered inthe signal evaluation; where integral to the assessment, this may include adescription of a case series or an individual case (e.g. an index case of welldocumented agranulocytosis or Stevens Johnson Syndrome)

discussion

conclusion



The EU single assessment

In order to increase the shared use of resources between

competent authorities in Member States, a single assessmentof PSURs shall be performed in the EU

A single EU PSUR assessment provides a mechanism forevaluating the totality of available data on the benefits

and risks of an active substance or combination of activesubstances.

The EU single assessment is the assessment of PSURs formedicinal products

subject to different marketing authorisations

containing the same active substance or the same combination of activesubstances

whether or not held by the same marketing authorisation holder

and for which the frequency and dates of submission of PSUR have beenharmonised in the list of EU reference dates



European Union reference date (EURD)

This corresponds to the date of the first or the earliestknown date of the marketing authorisation in the Unionof a medicinal product containing the active substance orcombination of active substances

EU reference dates list - a list of active substances and

combinations of active substances sorted in alphabeticalorder, for which PSURs shall be submitted in accordance withthe EU reference dates and frequencies determined by theCommittee for Medicinal Products for Human Use (CHMP) andthe Coordination Group for Mutual Recognition andDecentralised Procedures - Human (CMDh) following

consultation with the Pharmacovigilance and Risk AssessmentCommittee (PRAC)

The EURD list is available on the web portal of EMA



Frequency of the PSUR

The MAH is required to submit PSURs once a medicinal

product is authorised in the EU, even if it is not marketed

If the active substance contained in the medicinal product isnot listed on the EURD list, the MAH should continue tosubmit PSUR according to the condition in the MA if any,

otherwise according to the standard submission cycle:Immediately upon request

At least 6 monthly after authorisation and until the placing on themarket

At least 6 monthly for the first two years after being placed on themarket

Annually for the subsequent two yearsThereafter at three-yearly intervals

The EURD list is binding from DLPs as of1st April 2013



Timelines for submission

Marketing authorisation holders should submit to theAgency PSURs within 70 or 90 days from the datalock point:

within 70 calendar days of the data lock point (day 0) for PSURscovering intervals up to 12 months (including intervals of exactly12 months); and

within 90 calendar days of the data lock point (day 0) for PSURscovering intervals in excess of 12 months;

the timeline for the submission of ad hoc PSURs requested bycompetent authorities will be normally specified in the request,otherwise the ad hoc PSURs should be submitted within 90 daysof the data lock point.

Additional timelines provided due to the increasedcomplexity of the PSUR


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Interim Arrangements for submission of PSURs

Before the Agencys PSUR repository is in place

MAHs shall submit the PSURs to all competent authorities in MemberStates in which the medicinal products are authorised

For the substances or combination of active substances subject to asingle assessment or for which an EU reference date has beenestablished, the PSURs should be also sent to the Agency

The competent authorities in Member States requirements for thesubmission of PSURs during this transitional period are published in the

Agency web-site

From 12 months after the functionalities of the repository havebeen established and have been announced by the Agency, themarketing authorisation holders shall submit the PSURselectronically to the Agency

Once the structured electronic format ePSUR, based on contentagreed in the ICH-E2C(R2), becomes available, marketingauthorisation holders will have the possibility to submit PSURs andrelated documents automatically via an electronic gateway


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Evaluation of the PSUR

Day Action

Day 0 Start of the procedure according to the published timetable

Day 60 PRAC Rapporteurs preliminary assessment report

Day 90 MAH and PRAC members comments

Day 105 PRAC Rapporteurs updated assessment report (if necessary)

Day 120 PRAC recommendation adoption with the final PRAC assessmentreport

Day 134 CHMP opinion / CMDh position


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Transparency

Publication of PSUR-related documents on the European

medicines and national medicines web-portals

list of EU reference dates and frequency of submission of PSURs

final assessment conclusions of the adopted assessment reports

PRAC recommendations including relevant annexes

CMDh position including relevant annexes and where applicable, detailedexplanation on scientific grounds for any differences with the PRACrecommendations

CHMP opinion including relevant annexes and where applicable, detailed

explanation on scientific grounds for any differences with the PRACrecommendations

European Commission decision


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Quality Management System at MAH

Specific quality system procedures and processes shall be in place in order

to ensure the update of product information

Responsibility of the marketing authorisation holder to check regularly the list ofEU reference dates and frequency of submission published in the Europeanmedicines web-portal to ensure compliance with the PSUR reportingrequirements for their medicinal products

Systems should be in place to schedule the production of PSURs as perregulatory requirements and ad hoc requests

For those medicinal products where the submission of an RMP is not required,the marketing authorisation holder should maintain on file a specification ofimportant identified risks, important potential risks and importantmissing information in order to support the preparation of the PSURs

The marketing authorisation holder should have procedures in place to followthe requirements established by the Agency for the submission of PSURs.

The QPPV shall be responsible for the establishment and maintenance ofthe pharmacovigilance system


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Section 1Challenges in preparing the

PSUR


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New document, new requirements

Creation of a new process for producing the reportbased on new and additional data required fromdifferent stakeholders

New templateModular structure

E-submissions

Training of resourcesIdentification of concerned Departments

Identification of relevant personnel

Internal/External training

Maintaining complianceDocumentation

Internal/external audits


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Multi-functional involvement

Roles, responsibilities and timelines for gathering thedata required

Clear leadership

Early planning

Availability of personnel

Timely contributions by stakeholders

Peak workloads

Appropriate oversight if you consider outsourcing

Close collaboration

Commitment by different stakeholdersRegular communication

Agreement on conclusions


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Signal Management Process

Signal Detection processDocumented, compliant process and system

Timely follow-up of signalsTime & Resource constraints

Training

Overview of signalsClear ownership

Up-to-date information


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No globally accepted standards of benefit-riskmethodology

New requirement

Wide variation exists in the industry

Qualitative or Quantitative?


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Strategies for presenting thebenefit-risk analysis


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GVP Definition: Risk-benefit balance

An evaluation of the positive therapeutic effects ofthe medicinal product in relation to the risks [DIR2001/83/EC Art 1(28a)] (i.e. any risk relating to thequality, safety or efficacy of the medicinal product asregards patients health or public health [DIR2001/83/EC Art 1(28)]).


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GVP Module Guidance - Provide a clearexplanation of the methodology and reasoning

used to develop the benefit-risk evaluation:

The assumptions, considerations, and judgement orweighting that support the conclusions of the benefit-risk evaluation should be clear.

If a formal quantitative or semi-quantitative assessmentof benefit-risk is provided, a summary of the methodsshould be included.

Economic considerations (e.g. cost-effectiveness)should not be considered in the benefit-risk evaluation.


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ICH EC2 Benefit:Risk Assessment Method

Onlykey benefits and risks considered in the evaluationshould be specified

Context of use of the medicinal product

Benefit - consider its nature, clinical importance,

duration, and generalizability, as well as evidence ofefficacy in non-responders to other therapies andalternative treatments.

Risk - consider its clinical importance, e.g., nature oftoxicity, seriousness, frequency, predictability,

preventability, reversibility, impact on patients, andwhether it arose from off-label use, a new use, ormisuse.


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ICH EC2 Benefit:Risk Assessment Method (2)

Strengths, weaknesses, and uncertainties of theevidence should be considered when formulating thebenefit-risk evaluation.

Explanation of the methodology and reasoning used todevelop the benefit-risk evaluation

Comment on the feasibility of expressing benefitsand risks in such a way as to facilitate theircomparison.

If a formal quantitative assessment of benefit-riskis provided, a summary of the methods should be

included.Economic considerations (e.g., cost-effectiveness)

should not be considered in the benefit-riskevaluation.


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FTIHdecisionpoint

Ph 2bdecisionpoint

Commit toP3 decisionpoint

Filedecisionpoint

Development ActivitiesPost-Marketing Plan

Epidemiology disease info

Expected Actual use Target & actual use

pop.co-morbidities

Increased awareness in

target populationActual use population

Pre-clin data, Competitors,

Previous experience,

regulatory knowledge+ Phase I-II data

+ Phase II-III data + Post-marketing

experience

Pre-clin data, Competitors,

Previous experience,

regulatory knowledge

+ Phase I-II data,

Health

outcomes

+ Phase II-III data,

health economics

+ Post-

marketingexperience

Candidateselection

Disease specific

B:R profile (& model)B:R profile based on product facts

(reality profile)

D

isease

Risk

Be

nefit

P

rofile

Strategy

Systematic Benefit and Risk Assessment used to Build Development and Post-Marketing Strategy (2002)


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Eichler (EMA) DIA Annual Meeting June 2009


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Benefit-risk methodology project (2010)


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Qualitative Approaches

A generic qualitative approach of eight steps fordecision making, PrOACT, is presented as it might applyto decision-making by regulators, followed bydescriptions of three approaches currently underdevelopment: PhRMA BRAT, CMR CASS study and FDA

BRF.


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PrOACT

PROBLEM. Determine the nature of the problem and its context(approve/disapprove, restrict);

OBJECTIVES. Identify objectives that indicate the overall purposes tobe achieved (e.g., maximise favourable effects, minimiseunfavourable effects), and develop criteria against which thealternatives can be evaluated

ALTERNATIVES. Identify the options (actions about a medicinalproduct or the products themselves) to be evaluated

CONSEQUENCES. describe how the alternative would perform on thecriteria

TRADE-OFFS. Assess the balance between favourable andunfavourable effects.

UNCERTAINTY. Consider how the balance between favourable andunfavourable effects would change by taking account of the

uncertainty associated with the consequences.RISK. Judge the relative importance of the Agencys risk attitude forthis medicinal product and how risk would be

LINKED DECISIONS. Consider the consistency of this decision withsimilar past decisions, and assess whether taking this decision couldimpact future decisions


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A sub-discipline of operations researchthat explicitly considers multi-criteria indecision-making environments.7 steps that form a conceptual framework.

Establish the decision context.

Identify the options to be appraised.

Identification of the benefit and risk criteria & organization into a value tree.

Assessment of expected performance of each option against criteria.

Assign weights for each criterion to reflect relative importance.

Calculation of weighted scores at each level in hierarchy and overall.

Examination of results and sensitivity analysis.

Quantitative B-R Methods

MULTI-CRITERIA DECISION ANALYIS (MCDA)


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Current Scenario:

Systematic Structured Benefit:Risk Assessment isbecoming part of regulatory requirements in EU, USA,Japan

Qualitative approaches generally similar

Quantitative approaches - limited by ability to comparedissimilar health benefits and risks

MCDA provides modelling technique to comparedifferent benefits and risks, provides tools for sensitivityanalysis

EMA and other EU regulatory agencies working tounderstand decision making context


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Summary


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Summary

There has been a paradigm shift in the new format andcontent of the PSUR, legally required in the EU from Jan 2013and accepted in the other ICH regions - US and Japan

The sections on signal detection and benefit-risk analysispresent new challenges for the preparation of the PSUR

If a formal quantitative or semi-quantitative assessment ofbenefit-risk is provided, a summary of the methods should beincluded

The assumptions, considerations, and judgement or weightingthat support the conclusions of the benefit-risk evaluationshould be clear


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Questions


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Thank you for attending!

Hemendra Misra: [email protected]

Will Maier: [email protected]

benefit risk analysis

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